NZ534304A

NZ534304A - Formulations comprising psychotropic drugs and selenium

Info

Publication number: NZ534304A
Application number: NZ534304A
Authority: NZ
Inventors: Krishnarao Sitaramrao Vaddadi
Original assignee: Laxdale Ltd
Priority date: 2002-02-07
Filing date: 2003-02-04
Publication date: 2006-07-28
Also published as: WO2003066071A1; US6919330B2; US20030175361A1; TW200404558A; JP2005525329A; AU2003244454A1; GB0202900D0; WO2003066071A8; EP1478374A1

Abstract

Disclosed is the use of clozapine together with any biologically assimilable form of selenium in the manufacture of a medicament for the treatment or prevention of schizophrenia. The use of these compounds as a treatment for schizophrenia results in reduced incidence of cardiovascular disease in patients.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 534304 534 WO 03/066071 PCT/GB03/00490 1 FORMULATIONS COMPRISING PSYCHOTROPIC DRUGS AND SELENIUM Risk of cardiovascular illness is very common in patients who are also being treated for psychiatric and 5 neurological disorders. It is uncertain whether this is due to the underlying illness or whether it is due to the drugs which are used to treat that illness but many commentators have pointed out that the drugs themselves may precipitate cardiac arrhythmias, 10 myocarditis and cardiomyopathies. The information for doctors about drugs, particularly but not only ones for psychiatric and neurological disorders, authorised by regulatory authorities such as the United States Pood and Drug Administration (FDA) frequently contain 15 warnings about possible cardiovascular side effects. Clozapine is one drug which carries a high risk (GJ Killian et al, Lancet 1999; 354: 1841-5. L La Grenade et al, N Engl J Med 2001; 345: 224-5) . Clozapine can also cause depression of white cell 20 counts and in the worst cases complete loss of normal white blood cell production (agranulocytosis). The present invention relates to the co-administration of selenium together with a drug for the treatment or 25 prevention of psychiatric or neurological disorders and particularly with clozapine. The invention provides pharmaceutical formulations comprising a drug for the treatment or prevention of psychiatric or neurological disorders together with any biologically assimilable 30 form of selenium, such that when the drug is administered the daily dose of selenium is between 10 /xg and 2000 fig per day. Preferably, the daily dose of selenium provided by the 35 formulations of the present invention is between 50 /xg WO 03/066071 2 PCT/GB03/00490 and 500 /zg/day and very preferably between 150 and 300 jig/day. The selenium may be provided in the form of selenium 5 yeast, selenomethionine, selenocysteine or any appropriate selenite or selenate compound. This may form a component of the formulation. Alternatively the selenium may be chemically linked to the drug to form a selenium-drug derivative. 10 The drug of the formulations of the present invention is one used for the prevention or treatment of psychiatric or neurological disorders. The drug may be one approved by a regulatory authority for such a 15 treatment, including the US Food and Drug Administration (FDA) or the European Medicines Evaluation Agency (EMEA). The preferred invention is not to combine selenium with other multi-vitamin preparations, which have not been approved for 20 administration to patients with psychiatric or neurological disorders. Preferably, the drug is one used for the treatment or prevention of psychiatric disorders including schizophrenia and bipolar disorder. The drug clozapine is particularly suited for the 25 formulations of the present invention. The formulations are preferably orally administrable. In a second aspect of the invention, the selenium and 30 the drug may be formulated separately but provided in the same pack with instructions for co-administration. The present invention provides a pack containing the selenium and the drug packaged for co-administration. WO 03/066071 PCT/GB03/00490 3 In a third aspect of the invention there is provided a method for the treatment or prevention of any-neurological or psychiatric disease by the coadministration of a drug conventionally used to treat 5 that disease together with selenium in any biologically assimilable form in a daily dose of between 10 /tg and 2 000 /zg selenium per day. The treatment may be by separate administration of the drug and the selenium, or by administration of a formulation of the first 10 aspect of the invention. The invention further provides use of a formulation of the first aspect of the invention in the manufacture of a medicament for the treatment or prevention of any 15 neurological or psychiatric disease. The treatments are of psychiatric or neurological disorders. Preferably, the invention is used to treat psychiatric disorders including but not limited to 20 schizophrenia, bipolar disorder, depression, anxiety disorders and personality disorders. Alternatively, the invention is for the treatment or prevention of neurological disorders including but not limited to epilepsies, Parkinson's disease, dementias of both 25 Alzheimer and vascular types, Huntington's disease, spinocerebellar ataxias, Friedreich's ataxia, myotonic, dystrophy, amyotrophic lateral sclerosis and multiple sclerosis. 30 The present invention also provides a method for the reduction of side effects caused by administration of a drug for the treatment of a psychiatric or neurological disorder to a patient by the co-administration, separately or in a formulation according to the first 35 aspect of the invention, of the drug together with WO 03/066071 4 PCT/GB03/00490 selenium in any biologically assimilable form to provide a daily dose of between 10 fig and 2000 fig selenium per day. In most cases it is likely that the preferred range of selenium to used will be in the range of 50 to 500 /zg/day and very preferably in the range of 150 to 300 fig/ day. The present invention is described in particular with reference to the treatment of cardiovascular illness in patients who are also being treated for psychiatric and neurological disorders. The cause of the risk of developing this illness is unknown and multiple factors may be involved. One pilot study has reported that schizophrenic patients on clozapine, a drug, conventionally used to treat schizophrenia, have low selenium levels (LA Linday et al, J Clin Psychopharmacol 1995; 15: 353-60). This looked at only a few patients, however, did not analyse selenium in schizophrenic patients on other drugs, and did not look at selenium levels in patients with other disorders. For the present invention, a large study has been carried out in normal individuals, in patients with various mood disorders including depression and bipolar disorder, in schizophrenic patients on drugs other than clozapine, and in schizophrenic patients on clozapine. The results are shown in Table 1 below. Here the selenium levels are expressed in /xmol/litre and are shown as means plus or minus the Standard Error of the Mean (SEM) 4A followed by page 5 It is an object of the present invention to provide a formulation of any biologically assimilable form of selenium in a daily dose of between 10 |ig and 2000 |ig together with a drug such as clozapine in the manufacture of a medicament for the treatment or prevention of neurological or psychiatric disorders or at least provide the public with a useful alternative. WO 03/066071 5 PCT/GB03/00490 Table 1 Healthy controls Mood disorders Schizophrenia clozapine Schizophrenia other drugs N 56 36 .57 42 Mean age 43 .1 40.6 36.1 37.3 Plasma Se 1.49 ± 0.04 1.39 ± 0.05 1.28 + 0.04 1.47 ± 0.06 Red cell Se 1.80 ± 0.08 1.70 ± 0.07 1.47 ± 0.07 1.70 ± 0.07 5 This shows that all of the groups of patients, irrespective of what drugs they were on, exhibited low selenium levels, but that the levels were exceptionally low in the schizophrenic patients on clozapine. 10 Selenium is a constituent of many enzymes, particularly ones involved in antioxidant defences (MP Rayman, Lancet 2000; 232-240). Selenium deficiency leads to a particular risk of cardiovascular disease, especially myocarditis and cardiomyopathy. Selenium deficiency 15 also increases susceptibility to the serious cardiac complications of viral infections (MA Beck et al, Nature Medicine 1995; 1: 433-6). The present invention is based on the inventor's 20 suggestion that selenium deficiency is a major cause of the cardiovascular and perhaps other problems which are associated with the ingestion of drugs for psychiatric and neurological disorders, and especially clozapine where selenium will also be helpful in preventing the 25 depression of white cell counts and agranulocytosis. In order to reduce the risks of drug administration, it is now proposed that all drugs for neurological and 30 psychiatric disorders should be formulated with WO 03/066071 PCT/GB03/00490 6 sufficient selenium to prevent and correct any selenium deficiency. Though it is not clear why drugs so commonly are associated with selenium deficiency, it is now suggested that some of them increase selenium 5 excretion or impair selenium absorption into the body. It may therefore be necessary to incorporate levels of selenium into the drug formulation to provide a daily intake of selenium either around the normal daily requirement of selenium or, in appropriate cases, daily 10 intakes several times higher than that. Various official bodies have made recommendations about the usual daily selenium requirement (M Rayman 2000, Lancet 356: 233-241). These range from a low of about 15 50 /zg/day to a high of around 100 /zg/day. However, these figures do not take into account the possibility that drugs or illnesses may interfere with selenium absorption or excretion and the present invention therefore proposes that the broad range of selenium 20 supplementation needed by those taking therapeutic drugs may range from a low of 10 /zg/day in those whose selenium intakes are adequate or near adequate to a high of 2000 /zg/day in those who have particular problems with selenium metabolism or absorption. In 25 most cases it is likely that the preferred range of supplemental selenium to be added to the drug will be in the range of 50 to 500 /zg/day and very preferably in the range of 150 to 300 /zg/day. 30 This is illustrated by a further experimental study on giving selenium to patients with schizophrenia who were taking clozapine or other psychiatric drugs (see table 2) 35 WO 03/066071 7 PCT/GB03/00490 Table 2 - SELENIUM TREATMENT ■\.Age; .. .length. . Of illness;-.' : ; '-■■("v" ■ ^'...Diagnosis : i" Date:, {■: ^Plasma'-' . RBC '.."Se;/ ■•■'STOKKtOMT '<*• ..given ^ T '. MEmrGATrpii. Male 25 Since 1998 Schizophrenia 02/09/02 07/10/02 1.2 2.1 1.4 1.9 02/09/02 (200mcg) Clozapine 450mg nocte Female 26 Since 1992 Schizophrenia 02/09/02 07/10/02 1.2 2.3 1.9 2.4 12/09/02 (200mcg) Epilim 1000/d; 4mg/d; Zoloft 200mg/d; Marine 3g/d; Vitamin B Female 22 2 years + Schizophrenia 02/09/02 07/10/02 1.2 2.2 1.5 2.0 02/09/02 (200mcg) Clozapine 600mg/d; Epilim 2000mg/d; Logynon ED 1/d Male 41 25 years Schizophrenia Mild Autism 02/09/02 07/10/02 1.1 2.3 1.3 2.1 02/09/02 (200mcg) Clozapine 800mg/d; Losec 20mg/d; Clonazepam 3mg/d; Benzotropine 4mg/d; + laxatives Female 22 3 years Schizophrenia 03/05/02 7/06/02 11/07/02 1.3 1.0 1.2 1.0 1.0 1.3 05/06/02 (lOOracg) Risperidone 8mg/d; Levien ED 1/d; Quetiapine 400mg/d; Vitamin E lg/d; FGF Iron 1/d Male 22 4 years Schizophrenia 02/09/02 14/10/02 0.8 1.9 1.3 1.9 19/09/02 (200mcg} Clozapine 300mg/d; Epilim 1500mg/d Stelazine 5mg/d; Maxepa 4g/d; Ranitidine 300mg/d; Benzhexol 5mg/d; Maxalon 20mg/d; Lithium 500mg/d Male 28 Since May 2001 Schizophrenia 02/09/02 07/10/02 l.S 2.1 2.4 2.8 02/09/02 (200mcg) Clozapine 300mg nocte WO 03/066071 8 PCT/GB03/00490 f, Age' Length ' ■ ' bf .!■'•' Illness; ■ Diagnosis." ii:,bate. .-'Plasma'. •se-' ■■ rbc : Se\: !'. SEL Erj .i. U ■ GIVEN'.;' .^.^ICATiOW-1 Female 37 8 years Schizophrenia 02/09/02 07/10/02 1.1 2.5 1.5 2.4 02/09/02 (200mcgJ Clozapine 400mg/d; Citalopram 60; Zuclopenthixol 300mg I.M. 2/52; Tetnazepam lOmg/d; Lithium 900mg/d; Benzotropine 2mg/d Male 38 12 years Schizophrenia 02/09/02 07/10/02 1.2 2.4 1.6 2.3 02/09/02 (200mcg) Clozapine 700mg/d; Epilim 2g/d Nine patients were studied. Prior to treatment all patients had red cell and plasma selenium levels in the 5 lower part of the range for psychiatric patients. Eight of the patients were given 200/zg of selenium per day in the form of selenium yeast and one was given 100/ig per day. At the end of the supplementation period, all the eight patients who were given 200/zg per day showed 10 plasma and red cell selenium levels in the upper part of the range for normal individuals. However, the patient given 100 /ig per day showed no change in plasma selenium and only a small rise in red cell selenium. This indicates that for many patients 100/zg per day is 15 unlikely to be sufficient whereas 2 00/tg per day is likely to be sufficient giving rise to a preferred range of daily doses from 150/xg to 300/ig per day. The selenium may be provided in any form which may be 20 assimilated by the body. Many selenium supplements are prepared by growing yeast or possibly other microorganisms on selenium-containing medium and such yeast or other micro-organism derived sources would be appropriate. Selenium may also be chelated or 25 otherwise linked to a range of other conpounds, and in WO 03/066071 9 PCT/CB03/00490 particular amino acids. Selenomethionine and selenocysteine are common naturally occurring compounds which are widely used as selenium supplements. Inorganic salts of selenite and also selenate may be 5 used. Any assimilable form of selenium may be employed. The selenium may be incorporated into the actual drug delivery system whether that be tablets, liquids or 10 emulsions, hard or soft gelatin capsules, powders, drinks, foods or any other appropriate system which may be used by those skilled in the art to deliver either a drug or a selenium product. Usually the selenium will actually be incorporated into the drug formulation or 15 may be chemically linked to the drug to form a selenium-drug derivative. Sometimes it may be appropriate to provide the selenium in a separate formulation but linked to the drug in a combination package. 20 Example Formulations 1. A tablet formulation of any drug for a neurological or psychiaric disorder formulated together 25 with a selenium compound which delivers a daily amount of selenium between 10 fig and 2000 fig. The selenium may be in any biologically assimilable form including yeast selenium, selenomethionine, selenocysteine, sodium selenite or sodium selenate. 30 2. As in example 1 where the formulation is a hard or soft gelatin capsule 3. As in example 1 where the formulation is a liquid 35 or an emulsion with or without flavouring. WO 03/066071 PCT/GB03/00490 10 4. As in example 1 where the formulation is in any-other form appropriate for oral administration including a powder or a liquid. 5 5. As in examples 1-4 where the drug is clozapine or one of its derivatives. 10 6. As in examples 1-4 where the drug is any drug for the treatment of schizophrenia including but not limited to chlorpromazine, haloperidol, risperidone, olanzapine, quetiapine, zotepine, amisulpiride, ziprasidone, sertindole, ethyl eicosapentaenoate or 15 aripiprazole. 7. As in examples 1-4 where the drug is any drug for the treatment of depression including but not limited to amitriptyline, lofepramine, dothiepin, doxepin, 20 trimipramine, imipramine, clomipramine, protr iptyline, nortriptyline, venlafaxine, fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, reboxetine, mirtazepine, nefazodone, trazodone, moclobemide, viloxazine, maprotiline, phenelzine, 25 tranylcypromine or ethyl-eicosapentaenoate. 8. As in examples 1-4 where the drug is any drug for the treatment of bipolar disorder, including but not limited to lithium salts, valproic acid and its 30 derivatives and carbamazepine. 9. As in examples 1-4 where the drug is any drug for the treatment of anxiety including but not limited to any benzodiazepines, any beta-blockers and buspirone. 35 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 03/066071 PCT/GB03/00490 11 10. As in examples 1-4 where the drug is any drug for the treatment of epilepsy including but not limited to carbamazepine, lamotrigine, sodium valproate, phenytoin, benzodiazepines, barbiturates, topiramate, 5 gabapentin or vigabatrin. 11. As in examples 1-4 where the drug is any drug for the treatment of Parkinson's disease including but not limited to levodopa, benserazide, carbidopa, 10 selegiline, tolcapone, bromocriptine, ropinirole, apomorphine, pergolide, other dopamine receptor agonists, amantadine or anticholinergic drugs. 12. As in examples 1-4 where the drug is any drug for 15 the treatment of Huntington's disease, Friedreich's ataxia, myotonic dystrophy, amyotrophic lateral sclerosis, multiple sclerosis or any other neurodegenerative disease including but not limited to ethyl-eicosapentaenoate, riluzole, lofepramine and 20 cyclo-oxygenase 2 inhibitors. 13. As in examples 1-4 where the drug is any drug for the treatment of any form of dementia including but not limited to donepezil, rivastigmine, or gaiantamine or 25 any cholergic drug. 12 WHAT WE CLAIM IS:

1. Use of clozapine together with any biologically assimilable form of selenium in the manufacture of a medicament for the treatment or prevention of schizophrenia.

2. Use of clozapine together with any biologically assimilable form of selenium in the manufacture of a medicament for the treatment or prevention of schizophrenia, wherein the medicament provides a daily dose of selenium between 10|jg and 2000|jg per day.

3. The use according to claim 1, wherein the daily dose of selenium is between 50(jg and 500|jg per day.

4. The use according to claim 1, wherein the daily dose of selenium is between 150|jg and 300|jg per day.

5. The use according to claim 1, wherein the selenium is in the form of selenium yeast.

6. A use of clozapine together with any biologically assimilable form of selenium in the manufacture of a medicament for the treatment of schizophrenia substantially as herein described and with reference to any one of the accompanying examples 1 to 13. LAXDALE LIMITED By their Attorneys JAMES & WELLS lnic-~ o.iy </div>